Our proposed research is aimed at developing methods for evaluating prodrugs and designing prodrugs for topical drug delivery. In the present case, prodrugs of the antiviral agent, 9-beta-D-arabinofuranosyladenine (ara-A), will be investigated by means of a novel approach based upon concepts and techniques of physical chemistry which permit factoring out the various physical and biochemical processes influencing the delivery of the active form of the drug to the target sites. Transport and metabolism studies aimed at determining and/or predicting the target site concentrations of the ara-A species for a variety of recently synthesized ara-A prodrugs will be conducted in the hairless mouse skin and in the guinea pig and mouse vaginal membranes. The data analysis will involve the use of the recently developed methods of physical chemistry for handling the relatively complex problem of simultaneous diffusion and enzymatic reactions for a multicomponent system in biological membranes and tissues. Transport and metabolism studies aimed at determining intracellular levels of ara-A for ara-A prodrugs will also be conducted in mammalian cell suspensions. The data provided from the above studies will be compared to the results of antiviral efficacy experiments carried out with the prodrugs in tissue culture and in herpes virus infected animals (nude mouse skin, guinea pig vagina, and mouse vagina models). These data will lend themselves to an examination of the hypothesis that it is the ara-A species level at the target site which determines the efficacy of the prodrug. Because, also, the physical models employed in the data analysis yield physically significant parameters, the magnitudes of these parameters will be related to the molecular structures of the prodrugs; this information, in turn, could be used in the design of superior prodrugs.